The present invention pertains to the field of neoplastic diseases theraphy. In particular, the present invention refers to the synergic anticancer effect displayed by an anthracycline derivative administered in combination with at least another pharmaceutical substance effective in anticancer theraphy.
Cancers are a leading cause of death in animals and humans; surgery, radiation and chemotherapy are the useful means to fight cancers.
In particular, combined chemotheraphy, designed to treat cancer by using more than one drug in combination or association, is a well accepted modality of treatment of neoplastic diseases.
Several efforts have been and are still being undertaken in order to select antitumor combinations more and more active and safe to be administered to a patient suffering from a cancer.
The increase of the antitumor efficacy of a known antitumor compound by administering the same in combination with one or more different antitumor compounds in order to obtain a therapeutic synergy, is a strongly felt need in the field of anticancer theraphy.
The present invention fulfill such a need by providing an anthracycline derivative which a is morpholinyl anthracycline, administered in combination with at least another pharmaceutical substance effective in anticancer theraphy, so that a synergistic effect can be revealed.
It is therefore a first object of the present invention combined preparations comprising a morpholinyl anthracycline administered in combination with at least another pharmaceutical substance effective in anticancer theraphy chosen from an alkylating agent, an antimetabolite, a topoisomerase II inhibitor, a topoisomerase I inhibitor, an antimitotic drug and a platinum derivative.
Anthracycline derivatives according to this invention are morpholinyl anthracyclines having formula (I) and (II) 
The chemical names of the morpholinyl anthracyclines of formula (I) and (II) are 3xe2x80x2-deamino-3xe2x80x2-(2-methoxy-4-morpholinyl)doxorubicin. HCl (I), also known as methoxymorpholino doxorubicin (MMDX, internal code PNU 152243), and 3xe2x80x2-deamino-3xe2x80x2(4-morpholinyl)-13-deoxo-10-hydroxy-carminomycin (II), also known as MX2.
MMDX is a doxorubicin derivative obtained with the substitution of the -NH2 at position 3xe2x80x2 in the sugar moiety with a methoxymorpholino group. This compound, synthesised in the course of a research program aimed at identifying new anthracyclines with at least partially novel modes of action and possessing broad spectrum of activity, was disclosed and claimed in Bargiotti et al., U.S. Pat. No. 4,672,057.
MMDX is active in vitro and in vivo on tumor cells resistant to anthracyclines and presenting the mdr phenotype, this last mechanism being recognised to occur also in man.
No cross-resistance was observed on tumor cells resistant to L-PAM or cisplatin (cDDP), or on cells resistant to Topoisomerase II inhibitors (at-multidrug resistant).
MMDX is active after i.p., i.v. or oral administration, with good antitumor activity on murine leukemias, and on solid murine and human tumor models.
The compound differs from most anthracyclines in being highly potent when administered in vivo, the optimal i.v. dose being at least 80 fold less than that of doxorubicin.
The high lipophilicity of the molecule, which confers to the compound the ability to reach high intracellular concentrations and is most likely one of the reasons of its efficacy on resistant models, makes it effective also after oral administration.
MX2, a morpholinyl anthracycline belonging to the family of 3xe2x80x2-deamine-3xe2x80x2(4-morpholinyl) derivatives of 10-hydroxy-13-deoxocarminomycin, was described and claimed in Otake et al., U.S. Pat. No. 4,710,564.
MX2 is active in vitro and in vivo on tumor cells resistant to anthracyclines and presenting mdr phenotype.
No cross-resistance was observed on tumor cells resistant to CTX, L-Pam and cDDP.
MX2 is active in vivo after i.p., i.v. and oral administration, with good antileukemic and antitumor activity on murine and human tumor models. MX2 is highly lipophilic and less cardiotoxic than Doxorubicin. The major dose limiting factor of MX2 is myelosuppression.
Among pharmaceutical substances effective in anticancer theraphy which may be used in association or in combination with a morpholinyl anthracycline of formula (I) or (II) as defined above, there may be mentioned alkylating agents such as, e.g., mitomycin C, cyclophosphamide, busulfan, ifosfamide, isosfamide, melphalan, hexamethylmelamine, thiotepa, chlorambucil, or dacarbazine; antimetabolites such as, e.g., gemcitabine, capecitabine, 5-fluorouracil, cytarabine, 2-fluorodeoxy cytidine, methotrexate, idatrexate, tomudex or trimetrexate; topoisomerase II inhibitors such as, e.g., doxorubicin, epirubicin, etoposide, teniposide or mitoxantrone; topoisomerase I inhibitors such as, e.g., irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) or topotecan; antimitotic drugs such as, e.g., paclitaxel, docetaxel, vinblastine, vincristine or vinorelbine; and platinum derivatives such as, e.g., cisplatin, oxaliplatin, spiroplatinum or carboplatinum.
As used herein, xe2x80x9canticancer therapyxe2x80x9d refers to all types of therapies for treating cancers or neoplasms or malignant tumors found in mmls comprising humans, including leukemiae, melanoma, liver, breast, ovary, prostate, stomach, pancreas, lung, kidney, colon and central nervous system tumors.
The administration of the costituents of the combined preparations of the present invention can be made simultaneously, separately or sequentially.
It is therefore another object of the present invention the simultaneous, separate or sequential use of the combined preparations of the invention in anticancer theraphy.
As an example, a morpholinyl anthracycline of formula (I) or (II) as defined above can be administered before the other anticancer drug; a particular example refers to the morpholinyl anthracycline of formula (I) administered on day 1 and 2 followed by cisplatin on day 3.
A preferred combined preparation according to the invention comprises a morpholinyl anthracycline of formula (I) or (II) as defined above and a platinum derivative, in particular cisplatin. A more preferred combined preparation according to the invention comprises a morpholinyl anthracycline of formula (I) and cisplatin.
As already said, combined preparations according to the invention may be used in anticancer therapy. In a preferred embodiment, combined preparations of the invention may be useful for treating a liver cancer, for example a liver cancer primarily confined to the liver such as, e.g. an hepatocellular carcinoma or a cholangiocarcinoma, or liver metastases.
The costituents of the combined preparations according to the invention can be administered to a patient in any acceptable manner that is medically acceptable including orally, parenterally, or with locoregional therapeutic approaches such as, e.g., implants. Oral administration includes administering the costituents of the combined preparation in a suitable oral form such as, e.g., tablets, capsules, lozenges, suspensions, solutions, emulsions, powders, syrups and the like. Parenteral administration includes administering the costituents of the combined preparation by subcutaneous, intravenous or intramuscular injections. Implants include intra artherial implants, for example an intrahepatic arthery implant.
Injections and implants are preferred administration routes because they permit precise control of the timing and dosage levels used for administration.
For example, for treating a patient suffering from a liver cancer as defined above, simultaneous, separate or sequential intrahepatic administration of the costituents of the combined preparation may be performed via the hepatic arthery. More precisely, the costituents of the combined preparation may be administered to a patient with either a hepatic metastatic cancer, or with previously untreated primary liver carcinoma, via the hepatic arthery directly into the lateral entry of an i.v. line inserted into the bung of an intrahepatic potacath or via a catheter inserted into the hepatic artery.
In a particular embodiment of the present invention, MMDX may be administered via the hepatic arthery as an infusion; the appropriate dose of MMDX, preferably previously dissolved in saline solution, may be mixed with a suitable amount, for example an amount ranging from 1 ml to 100 ml of an agent, for example iodized oil (LIPIODOL(trademark)), which remains selectively in a liver tumor after its injection through the hepatic arthery. The actual preferred method and order of administration of the constituents of the combined preparation of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the morpholinyl anthracycline (I) or (II) as defined above being utilized, the particular pharmaceutical formulation of the other anticancer agent being utilized, the particular cancer being treated, the severity of the disease state being treated, and the particular patient being treated. The dosage ranges for the administration of the combined preparations according to the invention may vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art.
The dosage regimen must therefore be tailored to the particular of the patient""s conditions, response and associate treatments, in a manner which is conventional for any therapy, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions.